PROJECT SUMMARY Alzheimer?s disease (AD) is one of the most devastating international public health epidemics. There are currently no effective disease-modifying or preventative strategies. Current pathogenic models of AD emphasize a precipitating role of beta amyloid (A?) pathology, which stimulates tau deposition, neurodegeneration, and cognitive dysfunction. But recent work suggests that tau deposition frequently occurs prior to A?, could begin in midlife, and could be potentiated by other factors, including cerebrovascular disease. Tau pathology may play a role in AD racial/ethnic disparities, as the incidence and prevalence of AD is greater among African Americans and Hispanics, who have greater exposure to vascular risk factors and cerebrovascular disease. Thus, there are likely multiple pathways beginning in midlife that promote tau deposition and cognitive decline associated with AD, which may vary across racial/ethnic groups. The purpose of this study is to examine the extent to which tau deposition is related to cognitive function, to determine whether tau deposition varies across racial/ethnic groups, and to determine the extent to which cerebrovascular disease is associated with tau pathology in midlife. We will obtain tau positron emission tomography (PET) imaging among 150 middle-aged adults who are receiving high-resolution magnetic resonance imaging, A? PET, and comprehensive clinical evaluation as part of their participation in a study titled ?Offspring study of mechanisms for racial disparities in Alzheimer?s disease? (RF1 AG054070, MPI: J.J. Manly/A.M. Brickman). The aims of the proposed project are: 1. To determine whether tau pathology is associated with cognitive functioning in midlife. We hypothesize that increased tau deposition in the medial temporal lobes will be associated with poorer episodic memory functioning and odor identification deficits. 2. To determine whether tau pathology differs across racial and ethnic groups in midlife. We hypothesize that Hispanics and African Americans will have greater amounts of tau pathology relative to non-Hispanic Whites. 3. To determine whether markers of cerebrovascular disease are associated with tau pathology in midlife and whether race/ethnicity moderates this association. We hypothesize that magnetic resonance imaging-derived markers of cerebrovascular disease, including white matter hyperintensities, infarcts, and microbleeds, will be associated with increased tau. We also expect that the relationship between markers of cerebrovascular disease and tau pathology will vary across racial/ethnic groups. Successful completion of this study will potentially point to novel intervention targets for the prevention of AD in addition to identifying sources of racial/ethnic disparities in the disease.